Calcineurin regulation of neuronal plasticity

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Abstract

From the most basic of nervous systems to the intricate circuits found within the human brain, a fundamental requirement of neuronal function is that it be malleable, altering its output based upon experience. A host of cellular proteins are recruited for this purpose, which themselves are regulated by protein phosphorylation. Over the past several decades, research has demonstrated that the Ca2+ and calmodulin-dependent protein phosphatase calcineurin (protein phosphatase 2B) is a critical regulator of a diverse array of proteins, leading to both short- and long-term effects on neuronal excitability and function. This review describes many of the influences of calcineurin on a variety of proteins, including ion channels, neurotransmitter receptors, enzymes, and transcription factors. Intriguingly, due to the bi-directional influences of Ca2+ and calmodulin on calcineurin activity, the strength and duration of particular stimulations may cause apparently antagonistic functions of calcineurin to work in concert.

Section snippets

Inhibitor-1 and DARPP-32

A powerful mechanism by which CaN mediates diverse cellular effects is through the disinhibition of PP1. A serine/threonine phosphatase of broad specificity, PP1, is targeted to discrete subcellular locales proximal to its substrates throughout the brain [20]. The activity of PP1 is tightly regulated by several proteins including inhibitor-1 (I-1), which is expressed in various brain regions [21], [22], and the dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP-32), which is heavily

Cytoskeletal proteins

A key component of the neuronal cytoskeleton, microtubules are important for neuronal morphology, axonal transport, neurite outgrowth, and connectivity [36], [37], [38]. Microtubules are primarily composed of α- and β-tubulin, and microtubule-associated proteins (MAP) such as MAP2 and tau. The function of microtubules is largely influenced by dephosphorylation. For example, CaN dephosphorylation of tubulin, which is opposed by protein kinase A (PKA) and CaM-dependent protein kinase II (CaMKII),

Enzymes involved in neurotransmitter synthesis

The enzymes neuronal nitric oxide synthase (nNOS) and l-glutamate decarboxylase (GAD) have been identified as substrates for CaN modulation. Localized within post-synaptic terminals, nNOS synthesizes nitric oxide (NO) from l-arginine and molecular oxygen, leading to the activation of guanylyl cyclase (GC) and cGMP production [50], [51], [52]. NO is considered an unconventional neurotransmitter, as it freely diffuses across membranes, affecting GC-mediated signaling in proximal post-synaptic

Calcineurin regulation of activity-dependent gene expression

As described in the previous sections, rapid changes in synaptic strength are mediated by post-translational modifications of preexisting proteins. Enduring changes, however, are also dependent upon the induction of gene expression and protein synthesis [132], [133], [134]. CaN influences multiple transcription factors including MEF-2 [135], [136], [137], [138] and NF-κB [139]. Here we describe two mechanisms by which CaN regulates activity-dependent gene expression: (1) inhibition of CREB and

Summary

CaN exerts a powerful effect on a variety of signaling proteins within neurons. Depending upon the strength, duration, and site of a Ca2+ stimulus, CaN may either increase or decrease synaptic efficacy and cell excitability, through modulation of ion channels, neurotransmitter receptors, cytoskeletal proteins, kinases, other phosphatases, and transcription factors. Thus, in response to multiple forms of synaptic stimulation, CaN initiates both short- and long-term changes on neuronal function,

Acknowledgements

R.D.G. is supported by NIH training Grant DA07234. R.L.D. is supported by a Duke University post-doctoral fellowship. P.G.M. is supported by NIH Grant NS41302 and the Whitehall Foundation. The authors would like to thank Jeremy Bergsman, Karl Deisseroth, Geoffrey Pitt, Mark Thomas, and Ann Isaksen for the critical reading of the manuscript.

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